Historical Background

Kawasaki disease (KD) is one of the most common vasculitides of childhood. It has the potential to cause severe complications, significant morbidity, and even mortality. Expeditious treatment can largely prevent these complications, underscoring the importance of early and accurate diagnosis. The diagnosis is based on clinical criteria ( Box 35-1 ), and in the absence of a diagnostic test, correct identification of KD can be as exacting a challenge today as it has been for more than 40 years.

This vasculitis bears the name Kawasaki disease because of the highly detailed description of this illness in 50 children by Tomisaku Kawasaki in 1967. Scattered case reports of young children who died of ruptured or thrombosed coronary artery aneurysms have appeared in the medical literature since 1871. A clinical syndrome comprising most of the components of what is today recognized as KD was described by Munro-Faure in 1959 and by Itoga in 1960, and an even earlier fatal inflammatory vasculopathy primarily affecting young boys, infantile polyarteritis nodosa (IPN), likely represents extreme cases of the same disorder.

Definition and Diagnostic Criteria

KD is a self-limited vasculitis of unknown etiology characterized by fever, rash, conjunctivitis, oral mucositis, extremity changes, cervical lymphadenopathy, and, in a proportion of cases, dilation or aneurysms of the coronary and other arteries.

Criteria for the diagnosis of KD are shown in Box 35-1 . More recently proposed criteria include perineal rash in the criterion for changes in the extremities, and recognition that, in the presence of fever and coronary artery changes demonstrated by echocardiography, fewer than four criteria suffice to make the diagnosis of KD. Muta and colleagues showed that fewer cases of KD were missed when children were included whose fevers were abrogated with intravenous immunoglobulin (IVIG) within 5 days of the onset of fever.

None of these guidelines has 100% sensitivity and specificity for the diagnosis of KD. If a child has the characteristic clinical features and develops coronary artery aneurysms, the diagnosis is certain. Children who do not meet the criteria may have an incomplete or atypical form of KD (discussed later). Alternatively, some patients who fulfill all criteria may have other conditions. In a study of patients referred because of possible KD, Burns and colleagues found that the standard clinical diagnostic criteria for KD were fulfilled in 18 (46%) of 39 patients in whom other diagnoses were established. Furthermore, Benseler et al. found that in a consecutive series of children diagnosed with KD, up to one third had concurrent, identifiable infections, including Group A streptococcal tonsillitis, viral illnesses, pneumonia, and gastroenteritis.

More concerning from the perspective of trying to prevent disease sequelae is that many children who develop coronary artery aneurysms never meet criteria for KD. Witt et al. found in a single center study of 127 patients treated for KD that 36% did not meet the criteria for KD. Furthermore, the KD cases that did not meet the criteria for diagnosis had a significantly higher proportion of coronary artery abnormalities as compared to those cases that did meet criteria (20% vs. 7%, P < 0.05). Sudo et al. utilized epidemiological data from the twentieth nationwide survey of KD in Japan and found that the prevalence of coronary artery lesions 1 month after disease onset tended to be higher in the cases with one or two principal criteria as compared with those cases that had five to six criteria (7.4% vs. 2.5% P < 0.05). Consistent with this, a recent meta-analysis of over 20 studies of patients with KD found that incomplete KD is a risk factor for coronary artery abnormalities.

The youngest patients are the least likely to meet the classic criteria, and unfortunately they also have the highest risk of developing coronary artery abnormalities. Rosenfeld et al. found that up to 60% of children younger than 12 months old developed aneurysms in one series. For this reason, the diagnosis of KD should be considered in any infant with prolonged, unexplained fever, and there should be a low threshold for performing echocardiography in this age group. Conversely, in older children, treating KD is seldom an emergency, especially when patients present symptoms after only 5 or 6 days of fever. Observation of children older than 6 months who do not fulfill criteria may be the best course of action. The mean duration of fever in children with untreated KD is 12 days, much longer than typical viral illnesses, so the persistence of fever or development of additional signs of KD can be an indicator for treatment.

Epidemiology

Although worldwide in distribution, the incidence of KD is highest in Japan and is steadily increasing over time, although the reasons behind this increase are unclear. In 2010, the annual incidence rate recorded in Japan was 239.6 per 100,000 children aged up to 4 years, which is higher than during any of the three epidemics of KD in Japan in 1979, 1982, and 1986. Children of Japanese descent who reside outside Japan also face a higher risk of KD than do Caucasian children. The incidence is increasing in South Korea as well, with the second highest worldwide incidence of 134.4/100,000 children younger than 5 years of age in 2011. Rates in Taiwan and China are also high.

The epidemiology of KD in the United States differs from countries in Asia in that there are fewer cases (20.8/100,000 children <5 years in 2006) and the incidence does not seem to be rising over time. As assessed by hospital admissions in the U.S., children of Asian or Pacific Island ancestry have the highest incidence (30.3/100,000 <5 years). The incidence was intermediate for African Americans (17.5/100,00 <5 years) or children of Hispanic origin (15.7/100,000 <5 years), and lowest for whites (12/100,000 <5 years). In one large area of Great Britain, the annual incidence rate was 5.5 cases per 100,000 for children younger than 5 years old; the incidence for children of Asian ancestry was more than double that for Caucasian and African or Afro-Caribbean children.

KD is an illness of early childhood. Seventy-seven percent of affected patients are younger than 5 years old, with an average age of approximately 3 years, although there are reports of KD occurring in older children and adults. KD is more common in boys than in girls (male-to-female ratio of 1.36:1 to 1.62:1).

In Japan, the highest incidence occurs between 6 and 11 months old. In North America, the peak age at onset of KD is between 2 and 3 years old. In a recent Australian study of the years 2000 through 2009, the mean age of diagnosis was 4.2 years. The reasons for the geographic differences in age at onset are unclear.

Several reports document a seasonal incidence of KD. Burns et al. established a global seasonal pattern of KD with a peak in disease in January through March in the extratropical Northern Hemisphere. In Japan, the disease occurs most frequently in winter and spring months, with a nadir in October. In a study from Taiwan, the highest incidence was in the summer. In North America, cases have tended to occur between November and May. There were no seasonal variations in the incidence of KD in a study from western Australia. Although epidemics of KD were documented in Japan up to 1987, none has occurred since then.

In Japan, siblings of affected children have a risk of contracting KD that is approximately 10 times higher than the risk in the general population, but cases among children sharing the same home in other countries are uncommon. Dergun and colleagues reported 18 families in the United States with 24 affected members, including 9 sibling pairs. Second and even third attacks have been reported in a range of 1.5% to 3% of cases.

Etiology and Pathogenesis

The cause of KD remains unknown. Many of its epidemiological and clinical manifestations suggest an infectious origin. If an infectious agent does indeed cause KD, the putative organism would appear to be of very low communicability, or predominantly responsible for subclinical infections. Repeated attempts to identify a particular infectious trigger have been unsuccessful.

A predominance of immunoglobulin A (IgA)-secreting plasma cells in the blood vessel walls of children with fatal KD has suggested to Rowley and colleagues that an organism that gained entry through mucosal surfaces underlies the disease. No single pathogen is regularly demonstrable, although associations with Epstein–Barr virus (EBV), rotavirus, other viruses, and with bacteria have been reported. An association with a coronavirus was not confirmed. It is nonetheless a possibility that the vascular injury in KD may be the result of a direct cell-mediated attack on endothelial cells that are infected with an unidentified pathogen.

Other investigators have proposed that the vasculitis in KD is caused by either conventional antigens or superantigens that trigger an immune response to endothelial cells, rather than by direct infection of the vessels. Superantigens are produced by several bacteria, notably certain strains of Staphylococcus and Streptococcus, and are capable of stimulating large numbers of T cells in an antigen-nonspecific manner by interaction with the β chain of the T-cell receptor. Overrepresentation of T cells bearing Vβ2 among lymphocytes in coronary artery aneurysms, intestinal mucosa, and peripheral blood from patients with KD supports the hypothesized role of superantigens in the pathogenesis. A variety of additional circumstantial evidence and a murine model of Lactobacillus casei– induced vasculitis lend credence to this theory. Further, children with KD have unique reactions to mycobacterial antigens, which may also function as superantigens, including recall reactions at the site of a previous bacillus Calmette–Guérin immunization. Nonetheless, the only human illness definitively ascribed to superantigens is toxic shock syndrome, and different groups have published conflicting evidence regarding the isolation of superantigen-producing organisms, the detection of superantigen proteins, and the presence of an immunological signature of superantigen activity in patients with KD.

Additional clues to the cause of KD may come from humoral factors, including antiendothelial cell antibodies, circulating immune complexes, and antineutrophil cytoplasm antibodies (ANCAs) that are demonstrated by some researchers in a proportion of patients, but not by others. For example, findings from a murine model indicated that B cells may not be necessary for coronary arteritis. However, genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in the B lymphoid tyrosine kinase and CD40 genes as evidence that B cells may play a pathogenic role in KD.

Recent studies have demonstrated that regulation of T-cell activation may determine susceptibility to and severity of KD. Onouchi et al. identified a functional SNP in the inositol 1,4,5-triphosphate 3-kinase C (IPTKC) gene on chromosome 19 through linkage dis­equilibrium mapping. ITPKC acts as a negative regulator for T-cell activation, and the SNP was associated with risk for developing KD and coronary artery lesions. Supportive evidence for the role of T cells in KD has recently been provided via an animal model of KD, in which mice are injected intraperitoneally with Lactobacillus casei cell wall extract. T-cell costimulation was identified as a critical regulator of susceptibility to and severity of coronary arteritis in this model.

In the absence of confirmed evidence of a single etiological agent, a reasonable working hypothesis is that KD represents a stereotyped, pathological immune response to one or a variety of environmental and/or infectious triggers. It may be a form of reactive vasculopathy, like polyarteritis nodosa or Henoch–Schönlein purpura, with an inflammatory response developing in sterile tissues as a result of immune activation. Presumably, certain individuals are predisposed by virtue of their genetic constitution. The strong predilection for childhood onset may reflect the presence of developmental antigens that are targets for the inflammatory response only early in life, subtle maturational defects in immune responsiveness, or the timing of exposure to environmental triggers.

Genetic Background

In Japan, approximately 1% of patients with KD have a history of an affected sibling, and concordance for KD was 13.3% in dizygotic twins and 14.1% in monozygotic twins. Similarly, in Japan there is a significantly increased frequency of a history of KD in the parents of children with the disease. These observations indicate that there is a genetic predisposition to this disease, although the fact that affected twin pairs became ill within 2 weeks of each other also suggests an important role for an environmental agents.

The exact genetic factors that may underlie the disorder are unknown. Reported genetic associations have been reviewed by Hata and Onouchi. Candidate genes include those at the histocompatibility locus and those for other proteins involved in immunoregulation. Human leukocyte antigen (HLA) genes for B5, B44, Bw51, DR3, and DRB3*0301 have been associated with KD in Caucasians; Bw54, Bw15, and Bw35 in the Japanese; and Bw51 in Israelis. Onouchi and colleagues concluded that HLA polymorphisms contributed little to the pathogenesis of KD. However, a recent study identified an SNP that achieved genome-wide significance in the HLA-DQB2-HLA-DOB locus. There has been no reported association of any HLA antigen with the risk of coronary artery disease.

Polymorphisms of the tumor necrosis factor (TNF)-α gene (TNF), the IL 18 gene, the HLA E gene, and the gene for angiotensin-converting enzyme have also been associated with KD, but their pathogenic significance is disputed. A separate report implicated polymorphisms of the mannose-binding lectin (MBL) in the pathogenesis of KD. MBL binds to n-acetyl glucosamine and mannose present on the surface of many microbes. This interaction results in activation of complement (C3) independent of antibody. Levels of MBL are determined by polymorphisms of the MBL 2 gene and its promoters. Higher expression of MBL is associated with lower incidence of coronary artery lesions in patients under 1 year old, but it has the opposite effect in older patients. This apparent paradox is congruent with the belief that MBL is important in protecting the very young child from infectious diseases.

The gene controlling expression of inositol 1,4,5-triphosphate 3-kinase ( ITPKC ) has been identified as a susceptibility gene not only for KD, but also for coronary artery disease. This enzyme is strongly expressed by peripheral blood mononuclear cells and has an important role in inflammation by decreasing interleukin (IL)-2 expression. The functional polymorphism ITPKC 3 is significantly increased in patients with KD and coronary artery disease in Japanese and American populations. An SNP in the caspase-3 gene on chromosome 4 has also been associated with risk for IVIG resistance and coronary artery abnormalities, which may be due to its role in apoptosis. An SNP in the FAM167A-BLK gene is a recently identified locus that is significantly associated with a risk for KD. It is of interest, as previous studies have reported an association between SNPs in this region and autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus. There have also been reports of associations of functional SNPs in immunoglobulin receptor pathways and in the gene for CD40 .

Clinical Manifestations

Disease Course

The course of untreated KD may be divided into three phases ( Fig. 35-1 ): An acute, febrile period lasting for 10 to 14 days is followed by a subacute phase of approximately 2 to 4 weeks. This ends with a return to normal of the platelet count and erythrocyte sedimentation rate (ESR). The subsequent convalescent or recovery period lasts months to years, during which time vessels undergo healing, remodeling, and scarring.

Kawasaki disease can be viewed as an illness with acute, subacute, and recovery phases. The temporal characteristics outlined here are typical of the course of the disease.

(Adapted from Kawasaki T, Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children, Arerugi 16 (3) (1967) 178–222. [Article in Japanese].)

Acute Febrile Phase

The onset of fever in KD is characteristically abrupt, sometimes preceded by symptoms of an upper respiratory or gastrointestinal illness. Baker and colleagues studied the symptoms in the 10 days prior to diagnosis of KD in 198 patients. They reported that irritability occurred in 50%, vomiting in 44%, decreased food intake in 37%, diarrhea in 26%, and abdominal pain in 18%. Cough was reported in 28%, and 19% had rhinorrhea. In addition, 19% reported weakness, and 15% reported arthralgia or arthritis. Perineal desquamation may be another early sign of KD. Over the next 3 to 4 days, cervical adenitis, conjunctivitis, changes in the buccal and oral mucosa, a pleomorphic rash, and erythema and edema in the hands and feet develop. The manifestations occur in no particular order and can fluctuate in the first 7 to 10 days of illness. Accordingly, a thorough medical history is important for identifying subtle or transient manifestations of KD. Untreated, the clinical signs of KD subside after an average of 12 days. If myocarditis occurs, it often does so early and may be manifested by tachycardia, an S3 gallop, and perhaps signs of congestive heart failure. Pericarditis, abdominal pain, ascites, and hydrops of the gallbladder also may occur at this time.

Subacute Phase

After the acute phase, the child may be entirely asymptomatic if given IVIG. During this period, desquamation of the skin and specifically, periungual desquamation of the digits, may be the only clinically apparent residual feature. One in 13 children may develop arthritis of one or several joints during the late acute and subacute phases. Coronary artery aneurysms most commonly first develop during the subacute phase or occasionally earlier, but rarely later in children treated with IVIG. The irritability that can be quite prominent in the acute phase diminishes and resolves completely during the subacute phase.

Convalescent Phase

Most children are asymptomatic during the convalescent phase. The acute phase response has usually returned to normal, unless there are complications. Horizontal ridging of the nails (Beau lines), characteristic of many acute inflammatory conditions, may appear during this period.

Clinical Characteristics of the Classification Criteria

Fever

Fever, often exceeding 40°C (104°F), is the hallmark of KD. The fever is typically persistent and minimally responsive to antipyretic agents, tending to remain above 38.5°C (101.3°F) during most of the acute phase of the illness. It reflects elevated levels of TNF-α and IL-1, which are thought to mediate the underlying vascular inflammation. The diagnosis must be suspect in the absence of fever, though brief temperature spikes may be missed by fatigued or inexperienced parents.

Conjunctivitis

Bilateral, nonexudative bulbar conjunctivitis occurs in more than 85% of patients with KD. Conjunctival injection typically spares the limbus, which is the zone immediately around the cornea. However, the characteristic of limbal sparing is not required for conjunctival erythema to qualify as a diagnostic criterion. Inflammation of the palpebral conjunctiva is not prominent. Purulent discharge is especially unusual and suggests an alternative diagnosis.

Other ocular abnormalities also may occur, although they are not part of the diagnostic criteria. During the first week of illness, about three fourths of children are photophobic, a consequence of anterior uveitis, which peaks between 5 and 8 days of illness and is more common in children over 2 years old. Ocular inflammation usually resolves without specific therapy or sequelae. In exceptional instances, there may be posterior synechiae, scleral or conjunctival scarring, changes in the retina and vitreous, or even blindness.

Changes in the Lips and Oral Mucosa

Swollen, vertically cracked red lips and a strawberry tongue are characteristic of KD; the latter is caused by sloughing of filiform papillae and prominence of the large hyperemic fungiform papillae ( Fig. 35-2 ). Diffuse erythema of the oropharynx is also seen. Vesicles, ulcers, or tonsillar exudate suggest a viral or bacterial infection rather than KD.

A, The intense reddening, swelling, and vertical cracking of the lips are characteristic of Kawasaki disease (KD). B, The strawberry tongue of acute KD with hypertrophied papillae on an erythematous base and the peeling of the facial skin.

Exanthem

The cutaneous manifestations of KD are protean. Although the rash usually begins on the trunk, there is often a perineal confluence during the first days of the illness, followed by desquamation in the diaper area by day 6 in many cases. Macular, morbilliform, or targetoid lesions of the trunk and extremities are most characteristic. The rash is seldom pruritic, and vesicular or bullous lesions are rare ( Fig. 35-3 ). Psoriasis has been reported in several children with KD.

The nonspecific polymorphous rash is seen on the face arms and chest of this 2-year-old boy with acute Kawasaki disease.

Lymphadenopathy

Anterior cervical lymphadenopathy occurs during the acute phase of the disease, is usually unilateral, and may appear to involve only a single node. However, ultrasonography or computed tomographic imaging of the neck typically reveals grapelike clusters of enlarged nodes similar to those seen in EBV infections rather than the isolated adenopathy typical of bacterial adenitis. Occasionally, a node enlarges rapidly and may be mistaken for infectious lymphadenitis. After 3 or 4 days, it usually shrinks with or without specific therapy. Diffuse lymphadenopathy and splenomegaly are not typical of KD and should raise suspicions of a viral illness.

Extremity Changes

Indurated edema of the dorsum of the hands and feet and a diffuse red-purple erythema of the palms and soles occur early and last for 1 to 3 days. Sheetlike desquamation typically occurs 10 days or more after the start of the fever. It characteristically begins at the tips of the fingers followed by the toes, just below the distal edge of the nails ( Fig. 35-4 ). Flaky desquamation may occur elsewhere, but acral skin peeling usually occurs late in the course of KD and may be absent or inapparent. Consequently, it is more useful for retrospective confirmation of the diagnosis rather than for making therapeutic decisions.

A , Desquamation of the skin of the tips of the thumb and finger seen during the subacute phase of Kawasaki disease. B, Desquamation of the skin of the hand occurs later in the subacute and early recovery phase of the disease. In many children, the degree of desquamation is much less than is depicted here.

Incomplete Kawasaki Disease

Signs and symptoms in children who do not meet criteria for KD tend to parallel those of children who fulfill the diagnostic criteria. Incomplete KD is seen more frequently in young infants and older children, which is a critical observation as these groups of children are also at higher risk for coronary artery lesions. A particularly high level of suspicion is needed in infants younger than 1 year old. In a retrospective review of 45 cases of KD, 5 (45%) of 11 infants had incomplete disease, compared with 4 (12%) of 33 older children. In this study, coronary artery complications occurred in three older children (9%) but in seven infants (64%), including all five with incomplete disease. In view of these data, the American Heart Association (AHA) has suggested additional markers for identification of children who do not meet the classic criteria for KD but who might nonetheless be at increased risk for developing coronary artery aneurysms ( Fig. 35-5 ). Reports suggest that the algorithm recommended by the AHA committee performs well in reducing the number of children who are not treated for KD but who ultimately develop aneurysms.

Evaluation of suspected incomplete Kawasaki disease. ¹ In the absence of gold standard for diagnosis, this algorithm cannot be evidence based but rather represents the informed opinion of the expert committee. Consultation with an expert should be sought anytime assistance is needed. ² Infants 6 months old on day 7 of fever without other explanation should undergo laboratory testing and, if evidence of systemic inflammation is found, an echocardiogram, even if the infants have no clinical criteria. ³ Characteristics suggesting disease other than Kawasaki disease include exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider alternative diagnoses. ⁴ Supplemental laboratory criteria include albumin 3.0 g/dL, anemia for age, elevation of alanine aminotransferase, platelets after 7 d 450 000/mm ³ , white blood cell count 15 000/mm ³ , and urine 10 white blood cells/high-power field. ⁵ Can treat before performing echocardiogram. ⁶ Echocardiogram is considered positive for purposes of this algorithm if any of 3 conditions are met: z score of LAD or RCA 2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or 3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased LV function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2–2.5. ⁷ If the echocardiogram is positive, treatment should be given to children within 10 d of fever onset and those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation. ⁸ Typical peeling begins under nail bed of fingers and then toes.

(American Heart Association, Diagnosis, treatment, and long-term management of Kawasaki disease. Circulation 110 (2004) 2747–2771.)

Other Clinical Manifestations of Kawasaki Disease

Table 35-1 shows other clinical manifestations of KD.

TABLE 35-1

Manifestations of Kawasaki Disease

ORGAN SYSTEM	COMMON	UNCOMMON	FINDING SUGGESTS ALTERNATE DIAGNOSIS
Skin	Targetoid, urticarial, morbilliform rashes, livedo reticularis	Psoriasiform rash	Pustular, vesicular rashes
Lungs	Pleural effusion	Nodules, interstitial infiltrates
Urinary tract	Urethritis, pyuria	Hematuria, proteinuria, orchitis
Nervous system	Irritability, lethargy, anterior uveitis, sensorineural hearing loss	Seizure, stroke, cranial nerve palsy
Gastrointestinal system	Diarrhea, vomiting, hydrops of gallbladder, hepatomegaly	Intestinal hemorrhage, ruptured viscus
Hematological system	Anemia, thrombocytosis, leukocytosis	Thrombocytopenia, consumptive coagulopathy, hemophagocytic syndrome	Lymphocytosis *
Reticuloendothelial system	Anterior cervical lymphadenopathy	Posterior cervical, axillary lymphadenopathy	Diffuse lymphadenopathy, splenomegaly
Mucosa	Mucositis, glossitis, conjunctivitis		Discrete oral lesions, exudative conjunctivitis
Musculoskeletal system	Extremity edema, arthritis	Raynaud phenomenon
Cardiac system	Tachycardia, gallop rhythm, myocarditis, pericarditis	Coronary artery aneurysm, aortic root dilation, valvulitis

 

* Except during the convalescent phase.

Cardiovascular Disease

At onset, there is nearly always tachycardia, typically commensurate with the degree of fever. Early myocarditis occurs in at least one third to half of patients, and pericarditis also may occur. Myocardial involvement often leads to decreased contractility, commonly manifested by an S3 gallop that may become more prominent with hydration. Tachycardia out of proportion to the fever is also found in children with significant myocarditis. Such children may be misdiagnosed with viral myocarditis. In more severe cases, myocardial involvement may progress to dysrhythmias and signs of congestive heart failure. Children with prominent KD-associated myocarditis tend to respond briskly to treatment with IVIG, and long-term abnormalities of cardiac contractility are very uncommon in children treated appropriately during the acute phase of KD. Tacke et al. performed cardiac magnetic resonance (MR) imaging in patients and controls at a median of 11.6 years following diagnosis of KD and found that only those with severe coronary artery pathology had evidence of cardiac dysfunction.

Recently, there has been increasing awareness of a shocklike syndrome that can occur with KD (KD shock syndrome [KDSS]). Kanegaye and colleagues identified 13 children with systolic hypotension, which is a 20% or greater decrease in baseline systolic blood pressure, or clinical signs of poor perfusion from a cohort of 187 consecutive patients with KD at a single center. They found that a third of the children with KDSS had impaired left ventricular systolic function and nearly two thirds had coronary artery abnor­malities. IVIG resistance was also seen more commonly in the patients with KDSS. A Taiwanese group performed a case control study of 9 patients with KDSS compared with 27 season-matched controls and also found that the cases had a higher risk for coronary artery dilation.

The most significant and characteristic complication of KD, the development of coronary artery aneurysms in up to 25% of untreated patients, makes KD the leading cause of acquired heart disease among children in the developed world ( Figs. 35-6 and 35-7 ). Frank aneurysms are unusual early in the course of disease, but the lack of tapering seen on echocardiograms is typical, and coronary artery dimensions may be increased in the first 5 weeks after the disease first manifests. Interestingly, Muniz et al. compared coronary artery dimensions of febrile patients with non-KD illnesses to KD patients, and found that the non-KD febrile controls exhibited enlarged coronary artery dimensions, although not to the same degree as the KD cases. Similarly, Bratincsak found that no febrile controls had coronary artery diameters more than 2.5 standard deviations above the mean for age, size, and gender, a diameter typically reached by more than 10% of children with KD.

Echocardiographic demonstration of aneurysms of three coronary arteries in a child with Kawasaki disease. A , Aneurysms; CIRC , circumflex; LAD , left anterior descending coronary artery; RVOT , right ventricular outflow tract.

(Courtesy Dr. Dennis Crowley.)

A, Angiography of the coronary vessels in a 7-month-old boy with Kawasaki disease shows a huge aneurysmal dilation of the right coronary artery ( arrow ). B, Aneurysm of the left coronary artery in a 3-year-old girl with Kawasaki disease ( arrow ).

(Courtesy Dr. Zuidi Lababidi.)

The Japanese Ministry of Health (JPH) criteria use angiography or echocardiography to define coronary arteries as abnormal if the internal lumen diameter is greater than 3 mm in children younger than 5 years old or greater than 4 mm in children at least 5 years old. In addition, vessels are considered aneurysmal if the internal diameter of a segment measures at least 1.5 times that of an adjacent segment or the coronary artery lumen is clearly irregular. Aneurysms can be defined as small (an internal diameter of <5 mm), medium (an internal diameter of 5 to 8 mm) or giant (an internal diameter >8 mm) per the JPH.

Although coronary artery dimensions in normal children have been shown to increase linearly with body surface area (BSA) or length, the JPH criteria are not based on body size. Evaluation of coronary arteries in KD using age-, size-, and sex-adjusted indices (z scores) suggests that the incidence of abnormalities is higher than was generally recognized. Among patients classified as having normal coronary arteries by the JPH criteria, 27% had at least one BSA-adjusted coronary artery dimension more than 2 standard deviations above the mean. Of note, z scores are available only for the left main coronary artery, the left anterior descending artery, and the right coronary artery. Other coronary vessels can be assessed using the JPH criteria. Even children whose vessel dimensions are within the “normal” range may demonstrate a decrease in coronary artery diameter as they convalesce from KD. Some experts think that a z-score-based system of classifying aneurysms may be more discriminating, with a giant aneurysm defined as a z score of 10 or higher.

Coronary aneurysms may cause morbidity early in the course due to rupture or thrombosis, resulting in sudden death or myocardial infarction. Development of de novo coronary artery abnormalities more than 2 weeks after the end of the acute illness is unusual.

Although involvement of the coronary arteries is the most characteristic manifestation of the vasculitis of KD, other medium-sized muscular arteries also may be involved. Aneurysms of brachial and femoral arteries may be palpable clinically or demonstrable angiographically ( Fig. 35-8 ). In severe cases, peripheral arterial obstruction may lead to ischemia and gangrene. Visceral arteries are usually spared, although there are reports of gastrointestinal obstruction and acute abdominal catastrophe occurring because of vasculitis. Such complications generally arise in children with other signs of severe vasculitis, including aneurysms in coronary and peripheral arteries.

Angiographic study of a 2-year-old boy with severe Kawasaki disease resulting in multiple aneurysms of the coronary, axillary, iliac, and femoral arteries. The study revealed large aneurysms of the aorta and iliac arteries (A) and the femoral arteries ( B; arrows ). Aneurysms that were palpable in the axilla and groin in this patient later resolved.

(Courtesy Dr. G. Culham.)

Central Nervous System Complications

One of the most consistent clinical observations of children with KD, particularly in infants and very young children, is their extreme irritability. This probably represents the effect of aseptic meningitis and associated headache. Cerebrovascular accident and facial nerve paralysis have also been reported.

Musculoskeletal Disease

Arthritis was observed by Gong and colleagues in 7.5% of 414 children with KD. Arthritis was oligoarticular in 55% and polyarticular in 45%. Joints most commonly affected were (in order of decreasing frequency) knee, ankle, wrist, elbow, and hip. Joint pain was often severe, but responded to IVIG and high-dose aspirin in most instances. It may occur at any time during the disease course but has been described most commonly during the recovery phase. Arthritis in KD ultimately resolves, leaving no residua.

Respiratory Tract Disease

Cough, coryza, hoarseness, and otitis media frequently occur early in the course of the disease, and suggest a viral upper respiratory tract infection. Approximately one third of children have some degree of sensorineural hearing loss when tested within 30 days of fever onset. Salicylate toxicity may be responsible for transient cases, but sensorineural hearing loss of unclear etiology rarely may persist after aspirin is discontinued.

Gastrointestinal Tract Disease and Other Abnormalities

Abdominal pain is common, and approximately one fourth of children with KD have profuse, watery diarrhea during the acute febrile period. Abdominal distention may mimic mesenteric vasculitis or intussusception, and children with KD can present with an acute surgical abdomen, although this is rare. Segmental bowel wall thickening has been described in children with KD and abdominal pain, presumably reflecting visceral arteritis. The relatively common occurrence of hydrops of the gallbladder demonstrated by ultrasonography may aid in the diagnosis of incomplete KD. Occasionally, the gallbladder becomes large enough to be seen as a bulge in the anterior abdominal wall. The specificity of gallbladder distension is limited, however, and a dilated, engorged gallbladder may be seen in cases of streptococcal and staphylococcal infections, among other mimics of KD. Hepatosplenomegaly may occur in the absence of heart disease, or it may reflect cardiac failure.

Genitourinary Tract Involvement

Kidney and genitourinary tract involvement is uncommon but reported in KD. A study of 50 children with KD from Taiwan revealed hematuria (>5 red blood cells per high-power field [RBC/HPF]) in 6 patients, proteinuria (>100 mg/dL) in 5, and leukocyturia (>10 white blood cells per high-power field [WBC/HPF]) in 19. Renal ultrasonography was abnormal in five patients, and dimercaptosuccinic acid single photon emission computed tomography (DMSA SPECT) revealed inflammatory lesions in 26 children. Although renal function remained normal, scarring was demonstrated in 46% on repeated DMSA SPECT. Sterile pyuria is one of the supplemental laboratory criteria in the algorithm for suspected incomplete KD. Burns et al. compared pyuria in KD cases versus febrile controls without urinary tract infections. They found that pyuria was neither sensitive nor specific for KD, but that the magnitude of pyuria in KD was significantly higher than in febrile controls (42 WBC/µL vs. 12 WBC/µL).

Scrotal pain and swelling due to testicular inflammation are characteristic of pediatric vasculitides, including Henoch–Schönlein purpura, polyarteritis nodosa, and KD. Meatitis and dysuria also occur frequently during the acute phase of KD, and priapism has been described. Hemolytic-uremic syndrome, immune complex–mediated glomerulonephritis, and acute interstitial nephritis have each been reported in a few cases. Acute renal failure is a rare complication most commonly ascribed to complications of treatment with certain preparations of IVIG.

Differential Diagnosis

The differential diagnosis of KD includes viral and bacterial infections, toxin-mediated diseases, systemic-onset juvenile idiopathic arthritis and Stevens–Johnson syndrome ( Box 35-2 ). Viral illnesses such as measles (especially when atypical or occurring after vaccination), EBV, and adenovirus infections share many of the signs of mucocutaneous involvement, but they typically have less evidence of systemic inflammation and generally lack the extremity changes of KD. Toxin-mediated illnesses, especially scarlet fever, staphylococcal scalded skin syndrome, and toxic shock syndrome lack the ocular and articular involvement typical of KD. Drug reactions, such as those in Stevens–Johnson syndrome or serum sickness, may mimic KD but have subtle differences in the ocular and mucosal manifestations. In particularly severe or prolonged KD, the possibility of a chronic vasculitis such as polyarteritis nodosa must be considered carefully. A lack of renal involvement and presence of mucocutaneous changes favor the diagnosis of KD over polyarteritis nodosa.

Pathology

The signs and symptoms of KD are due to a systemic necrotizing vasculitis with fibrinoid necrosis of the medium-sized muscular arteries; the coronary arteries are the predominant sites of involvement. Disruption of the lamina elastica is characteristic of the aneurysms. Fujiwara documented early neutrophilic infiltrate in all layers of the heart, including the valves. Inflammation begins in the microvasculature (i.e., arterioles, capillaries, vasa vasorum, and venules) and subsequently spreads to larger vessels, especially the coronary arteries. In these lesions, infiltrating cells are mostly macrophages and IgA-secreting plasma cells, findings that may be unique to KD. Endothelial cells express a variety of markers of activation, presumably as a result of the high levels of proinflammatory cytokines that characterize the acute phase of disease. Some children have a lymphocytic myocarditis, with endomyocardial biopsy demonstrating cellular infiltrates or myofibrosis that may persist for years in untreated cases.

Evolution of the cardiac lesions was detailed in the study by Fujiwara and Hamashima. Pericarditis, myocarditis, and endocarditis were universal findings early in the disease, but diminished as fibrosis of the myocardium became the predominant lesion in children whose death occurred 40 days or more after onset. Coronary artery vasculitis predominated early in the disease but was absent in those who died after 28 days of illness. Aneurysms, thrombosis, and stenosis did not appear until 12 days of disease or later.

In a study of 262 children, Suzuki and colleagues documented an equal frequency of aneurysms in the right and left coronary arteries, but a higher propensity for development of segmental stenosis and occlusions in the right coronary artery.

Using light and electron microscopy, Orenstein et al. reviewed autopsy and cardiac transplant tissues from KD patients, and described three phases to the arteriopathy of KD that differ in some ways from prior descriptions. The first phase is characterized by a neutrophilic necrotizing arteritis that begins in the endothelium and can cause saccular aneurysms as the process moves through the walls of the arteries to the adventitia in the first 2 weeks of illness. This is followed by a subacute or chronic vasculitis driven by lymphocytes, plasma cells, and eosinophils that may last weeks to years and results in fusiform aneurysms. During the subacute or chronic vasculitis, smooth muscle cells may be converted to myofibroblasts that cause progressive stenosing lesions, leading to thrombosis.

Laboratory Examination

There are no specific diagnostic tests for KD, but at onset, evidence of inflammation is manifested by elevation of C-reactive protein (CRP) and ESR, leukocytosis, and a left shift in the white blood cell (WBC) differential count. Toxic granulation of neutrophils is more frequent in children with KD than in those with other febrile illnesses. Occasionally, significant neutropenia occurs early ; this may be a marker for particularly severe disease. Thrombocytopenia and anemia may herald the onset of macrophage activation syndrome (see Chapter 49 ). Although platelet counts may be normal at the onset of disease, by the second week of illness they characteristically rise and may reach 1,000,000/mm ³ (reactive thrombocytosis) in the most severe cases. Children with KD often present with a normocytic, normochromic anemia; hemoglobin concentrations greater than 2 standard deviations below the mean for age are found in half of patients within the first 2 weeks of illness.

Sterile pyuria is of urethral origin and therefore is missed on urinalyses obtained by bladder aspiration or catheterization. The WBCs are mononuclear and are not detected by dipstick tests for leukocyte esterase. Measurement of liver enzymes often reveals elevated transaminase levels or mild hyperbilirubinemia due to intrahepatic congestion. A few children develop obstructive jaundice from hydrops of the gallbladder or hepatic vasculitis.

Cerebrospinal fluid (CSF) analysis typically displays a mononuclear pleocytosis with normal glucose and protein. In a chart review of 46 children with KD, 39% were documented to have elevated CSF WBC counts. The median count was 22.5 cells/mm ³ with 6% neutrophils and 91.5% mononuclear cells, although cell counts as high as 320/mm ³ with up to 79% neutrophils were reported. Arthrocentesis of involved joints typically demonstrates synovial fluid WBC counts of 50 to 300,000 WBC/mm ³ consisting primarily of neutrophils.

Children with KD develop significant perturbations in serum lipid profiles beginning during the subacute phase of illness. These abnormalities include elevated concentrations of triglycerides and low-density lipoproteins, and depressed levels of high-density lipo­proteins. They are most likely caused by widespread endothelial injury, and persistent abnormalities in lipid profiles are more likely in those children with coronary artery abnormalities. Ou et al. found that 1 year after the onset of KD, children with coronary artery aneurysms were more likely to have depressed high-density lipoprotein cholesterol levels and elevated high-sensitivity CRP levels than those KD patients who had normal coronary arteries. As with other sequelae of KD, normalization may take years in untreated children but typically occurs within weeks or months after IVIG therapy.

ANCAs and antibodies to endothelial cells may be present late but not early in the disease. Consequently, they have unclear pathological significance and are of little diagnostic value. Other autoantibodies are usually absent. Elevated levels of von Willebrand factor antigen indicate the presence of damaged endothelium. Activation products of C3 and C4 have been demonstrated on erythrocytes (C3g) and in the plasma (C4d), suggesting the participation of complement in at least some of the manifestations of the disease.

Treatment

Intravenous Immunoglobulin

Furusho and co-workers first reported that high-dose IVIG appeared to decrease the incidence of coronary artery abnormalities. Newburger and colleagues verified these findings in a 19-month, randomized, controlled clinical trial in 168 children with KD. Half of the children received IVIG (400 mg/kg/day on 4 consecutive days) plus high-dose aspirin (100 mg/kg/day), and half of the children received aspirin alone. IVIG reduced the incidence of coronary artery abnormalities by 78%, and no child suffered serious adverse effects from the therapy, thereby confirming the remarkable therapeutic potential of IVIG.

The initial IVIG treatment regimen was based on then-current protocols for treating immune thrombocytopenic purpura. The question of whether this protocol was optimal for KD was addressed in 1991. Children were randomized to receive the traditional four-dose regimen or a single dose of 2 g/kg of IVIG infused over 8 to 12 hours. Children receiving the larger, single dose fared better. Meta-analyses have documented a dose-response benefit of IVIG therapy in the range of 200 mg/kg to 2 g/kg.

IVIG is most effective in reducing the risk of coronary artery disease when administered within 10 days of the onset of fever. Unfortunately, the diagnosis may remain in doubt as this deadline approaches. In ambiguous cases, the physician may be guided by the epidemiology of the disease. More than 50% of infants with KD present atypically (i.e., do not fulfill diagnostic criteria), and they have a very high incidence of aneurysms. Thus, empiric treatment in very young children warrants serious consideration.

The mechanism of action of IVIG is uncertain, with studies adding induction of neutrophil apoptosis and reversal of inhibited lymphocyte apoptosis to a long list of immunomodulatory effects of IVIG ( Box 35-4 ). The response is generally prompt, and temperature returns to normal in many children even before the end of the IVIG infusion, with rapid clearing of the rash, mucositis, and conjunctivitis. Irritability and emotional lability, however, may persist for up to several weeks before resolving.

Box 35-4

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